The present invention relates to methods and pharmaceutical compounds and compositions for stimulating neurite outgrowth in nerve cells leading to nerve regeneration. For example, the compositions comprise compounds that inhibit the peptidyl-prolyl isomerase (rotamase) enzyme activity associated with the FK-506 binding proteins (FKBP), such as FKBP 12 and FKBP 52. The methods comprise treating nerve cells with compositions comprising the rotamase-inhibiting compound. The methods of the invention can be used to promote repair of neuronal damage caused by disease or physical trauma.
Inmunophilins are a family of soluble proteins that serve as receptors for important immunosuppressant drugs such as cyclosporin A, FK-506 and rapamycin. An immunophilin of particular interest are the FK-506 binding proteins (FKBP). For a review of the role of immunophilins in the nervous system, see Solomon et al., xe2x80x9cImmunophilins and the Nervous System,xe2x80x9d Nature Med., 1(1), 32-37 (1995).
The 12-kiloDalton FK-506 binding protein, FKBP12, binds FK-506 with high affinity. Such binding has been directly measured using microcalorimetry and radiolabeled FK-506, e.g., [3H]dihydro-FK-506 (see Siekierka et al., Nature, 341, 755-57 (1989); and U.S. Pat. No. 5,696,135 to Steiner et al.) and 32-[1-14C]-benzoyl-FK-506 (see Harding et al., Nature, 341, 758-60 (1989)). Binding affinity of other compounds for FKBP can be determined directly by microcalorimetry or from competitive binding assays using either tritiated or 14C-labelled FK-506, as described by Siekierka et al. or Harding et al.
FK-506-binding protein FKBP12 participates in a variety of significant cellular functions. FKBP12 catalyzes cis-trans isomerization of peptidyl-prolyl linkages. This peptidyl-prolyl isomerase enzyme activity is also referred to as rotamase activity. Such activity is readily assayed by methods known in the art (see Fischer et al., Biochim. Biophys. Acta 791, 87 (1984); Fischer et al., Biomed. Biochim. Acta 43, 1101 (1984); and Fischer et al., Nature 337, 476-478 (1989)). U.S. Pat. Nos. 5,192,773 and 5,330,993 to Armistead et al. report FKBP binding affinities that were correlated with rotamase-inhibiting activities for many compounds.
FK-506 and compounds that bind FKBP competitively with FKBP stimulate outgrowth of neurites (axons) in nerve cells (see U.S. Pat. No. 5,696,135 to Steiner et al.). Lyons et al. (Proc. Natl. Acad, Sci, USA, 91, 3191-95 (1994)) demonstrated that FK-506 acts to enhance or potentiate the effectiveness of nerve growth factor (NGF) in stimulating neurite outgrowth in a rat pheochromocytoma cell line. The mechanism of stimulation of such neurite outgrowth appears to be 10- to 100-fold potentiation of the action of nerve growth factor.
Potency for inhibition of the peptidyl-prolyl isomerase (rotamase) enzyme activity of FKBP by FK-506, and by compounds that competitively inhibit FK-506 binding to FKBP, empirically correlates with activity for stimulation of neurite outgrowth. Because of the close correlation between rotamase inhibition and neurotrophic action, it has been proposed that the rotamase may convert a protein substrate into a form that promotes neural growth (see U.S. Pat. No. 5,696,135). For example, it has been found that FKBP12 forms bound complexes with the intracellular calcium ion channelsxe2x80x94the ryanodine receptor (RyR) and the inositol 1,4,5-triphosphate receptor (IP3R) (Jayaraman et al., J. Biol. Chem., 267, 9474-9477 (1992); Cameron et al., Proc. Natl. Acad. Sci, USA, 92, 1784-1788 (1995)), helping to stabilize calcium release. For both the RyR and the IP3R, it has been demonstrated that FK-506 and rapamycin are capable of dissociating FKBP12 from these receptors. In both cases, the xe2x80x9cstrippingxe2x80x9d off of FKBP12 leads to increased leakiness of the calcium channels and lower intracellular calcium concentrations. It has been suggested that calcium flux may be associated with stimulation of neurite outgrowth.
In addition, FK-506xe2x80x94FKBP bound complexes bind to and inhibit calcineurin, a cytoplasmic phosphatase. The phosphatase activity of calcineurin is necessary for dephosphorylation and subsequent translocation into the nucleus of nuclear factor of activated T-cells (NF-AT) (see Flanagan et al., Nature, 352, 803-807 (1991)). NF-AT is a transcription factor that initiates interleukin-2 gene activation, which in turn mediates T-cell proliferation; these steps are important to the activation of an immune response. Calcineurin-inhibiting activity is correlated with the immunosuppressant activity of FK-506 and related compounds.
Calcineurin inhibition, however, does not correlate with the stimulation of neurite outgrowth. Therefore, compounds that are potent inhibitors of rotamase but not strong inhibitors of calcineurin are desired since they should be neurotrophic but non-immunosuppressive.
Such neurotrophic agents desirably find use in augmenting neurite outgrowth, and hence in promoting neuronal growth and regeneration in various pathological situations where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or diseases such as diabetes, brain damage associated with stroke, and for the treatment of neurological disorders related to neurodegeneration, including Parkinson""s disease, Alzheimer""s disease, and amyotrophic lateral sclerosis (ALS).
Such neurotrophic agents should also be useful for the treatment of memory impairment, for the treatment of hair loss, for the treatment of hearing loss, and for the treatment of vision disorder. See WO 00/16603 and WO 00/32588. Further, such use is preferably without the associated effect of immunosuppression, since long-term use of immunosuppressants is associated with side effects such as kidney toxicity, neurological deficits, and vascular hypertension.
Various inhibitors of rotamase enzyme activity, FKBP-binding compounds, or immunomodulating compounds are known. See, e.g., U.S. Pat. Nos. 5,192,773; 5,330,993; 5,516,797; 5,612,350; 5,614,547; 5,622,970; 5,654,332; 5,665,774; 5,696,135; 5,721,256; 5,798,355; 5,786,378; 5,846,979; 5,801,187; 5,801,197 and 6,080,753. See also EP 947,506 and International Publication Nos. WO 96/41609, WO 96/40633, WO 96/40140, WO 98/29116, WO 98/29117, WO 97/14439, WO 98/37882, WO 99/45006, WO 00/27811, WO 00/09102, WO 00/05232, WO 00/46181 and WO 99/6251.
In view of the variety of disorders that may be treated by stimulating neurite outgrowth and the relatively few neurotropic agents having an affinity for FKBP-type immunophilins, there remains a need for additional neurotrophic agents. In particular, there is a need for those neurotropic agents that are potent inhibitors of the enzyme activity and especially of the cis-trans propyl isomerase (rotamase) activity of the FKBP-type immunophilins, particularly the immunophilin FKBP-12. Such compounds will desirably have physical and chemical properties suitable for use in pharmaceutical preparations, e.g., bioavailability, half-life, and efficient delivery to the active site. In view of the desired properties, small organic molecules are preferred over proteins. Furthermore, such compounds will not significantly inhibit the protein phosphatase calcineurin and therefore lack any significant immunosuppressive activity.
According to International Publication Nos. WO 00/46181 and WO 00/46222, binding to FKBP is not necessary for neuronal activity.
It is therefore an object of the invention to provide small-molecule neurotrophic compounds, preferably through affinity for FKBP-type immunophilins. Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins, particularly rotamase enzyme activity. An additional object is to provide inhibitor compounds of the present invention that do not exert any significant immunosuppressive activity in addition to their neurotrophic activity. It is a further object of the invention to provide effective processes for synthesizing such compounds as well as useful intermediates therefore. Another object of the invention is to provide methods for treating patients having neurological trauma or disorders as a result of, or associated with, conditions that include (but are not limited to) neuralgias, muscular dystrophy, Bell""s palsy, myasthenia gravis, Parkinson""s disease, Alzheimer""s disease, multiple sclerosis, ALS, stroke and ischemia associated with stroke, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries. Another object of the invention is to provide methods for treating patients with hair loss, vision disorder, memory impairment, and hearing loss.
Such objects have been achieved by the neurotrophic compounds of the present invention, which maybe used to stimulate the growth and regeneration of neurons. The administration of these compounds to individuals requiring therapeutic stimulation of neuronal growth and regeneration provides effective therapies in various pathological situations where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or disease such as diabetes, brain damage associated with stroke, and for the treatment of neurological disorders related to neurodegeneration, including Parkinson""s disease, Alzheimer""s disease, and amyotrophic lateral sclerosis.
To achieve these and other objectives, as embodied and broadly described, in a first aspect, the present invention relates to a compound of formula (I): 
or a pharmaceutically acceptable salt, solvate, pharmaceutically acceptable prodrug or pharmaceutically active metabolite thereof, wherein:
A is C3-C5 alkylene optionally substituted with one or more suitable substituents and optionally any one of the CH2 groups of the alkylene group may be replaced by O, S, SO or SO2; 
where E and G are independently Ar, H, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkyl or alkenyl that is substituted with a C5-C7 cycloalkyl, C1-C6 straight or branched alkyl or alkenyl that is substituted with a C5-C7 cycloalkenyl, or Ar substituted with C1-C6 straight or branched alkyl or alkenyl, wherein, in each case, one or two of the CH2 groups of the alkyl or alkenyl chains may be replaced by 1-2 moieties selected from the group consisting of oxygen, sulfur, SO, SO2, and 
where J is H, C1-C6 straight or branched alkyl, or C1-C6 straight or branched alkenyl; and
K is Ar or substituted 5-7 membered cycloalkyl with substituents at positions 3 and 4 which are independently selected from the group consisting of H, OH, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94alkyl, xe2x80x94Oxe2x80x94(CH2)m-alkenyl and carbonyl, wherein m is 1-4;
where Ar is selected from the group consisting of unsubstituted and substituted phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and monocyclic and bicyclic heterocyclic ring systems with each ring having 5 or 6 ring atoms optionally, including 1-4 heteroatoms independently selected from O, N and S; wherein when substituted, the substitutents are from one to three substituents independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, Oxe2x80x94(C1-C4 straight or branched alkyl), Oxe2x80x94(C2-C4 straight or branched alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl; and n is an integer from 0 to 4;
D is C1-C6 straight or branched alkyl, C1-C6 straight or branched alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched alkyl or C1-C4 straight or branched alkenyl, [(C2-C4)-alkyl or (C2-C4)-alkenyl)]-Ar, or Ar; and X is NR10 or O, where R10 is H, C1-C4 alkyl, or C1-C4 alkenyl.
In a second aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
In a third aspect, the invention relates to a method of treating a neurological disorder in an animal, comprising administering to the animal a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt, prodrug, solvate, or its pharmaceutically active metabolite.
In a fourth aspect, the invention relates to processes of making the compounds of formula (I).
In a fifth aspect, the invention relates to a method of treating hair loss, memory impairment, or vision disorder in an animal comprising administration to the animal a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt, prodrug, solvate, or its pharmaceutically active metabolite.
In a sixth aspect, the invention relates to compounds of formula (II): 
and pharmaceutically acceptable salts, prodrugs, solvates, or pharmaceutically active metabolites thereof, wherein:
Jxe2x80x2 is hydrogen, or substituted or unsubstituted alkyl;
Kxe2x80x2 is substituted or unsubstituted alkyl; or Jxe2x80x2 and Kxe2x80x2 taken together with the adjacent nitrogen atom form a heterocycle ring which may contain another heteroatom;
M is selected from the group consisting of xe2x80x94OR1, 
wherein:
R1 is hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or cycloalkenyl, or C(R11)(R12)(R13), wherein R11 and R12 each independently is substituted or unsubstituted alkyl, or R11 and R12 together with the atom to which they are bound form a cycloalkyl, and R13 is H, OH, substituted or unsubstituted alkyl, aryl, heteroaryl, heterocycloalkyl, or (CH2)nxe2x80x94Oxe2x80x94W1, where n is 0, 1, 2, or 3, W1 is R or C(O)R2, and R2 is substituted and unsubstituted alkyl;
Rxe2x80x2 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, hydroxyl, and amino; or
R1 and Rxe2x80x2 taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle;
Rxe2x80x3 is hydrogen or substituted or unsubstituted alkyl; or
R1 and Rxe2x80x3 taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle;
Lxe2x80x2 is 
wherein Xxe2x80x2 is selected from O, S and N;
Yxe2x80x2 is selected from O, NH, S, a direct bond, and NRf, wherein Rf is substituted or unsubstituted alkyl; or
Xxe2x80x2 and Yxe2x80x2 taken together with the adjacent carbon atom form a heterocycle ring; or
the Lxe2x80x2 NSO2M moiety of formula (II) forms a 5-membered-cyclic sulfamide ring;
Bxe2x80x2 is hydrogen or 
where n is an integer from 0 to 4;
Exe2x80x2 and Gxe2x80x2 are independently H, substituted or unsubstituted alkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, cycloalkyl, or cycloalkenyl, wherein, in each case, one or two of the CH2 groups of the alkyl or alkenyl chains may be replaced by 1-2 moieties selected from the group consisting of oxygen, sulfur, SO and SO2, or 
where Qxe2x80x2 is H, or substituted or unsubstituted alkyl or alkenyl; and
Q is substituted or unsubstituted cycloalkyl, heterocycloalky, aryl, or heteroaryl;
Ra and Rb are independently hydrogen, substituted or unsubstituted alkyl or cycloalkyl;
Z is O, NH, CH2 or NRe, wherein Re is substituted or unsubstituted alkyl; and
Rc and Rd are independently hydrogen, 
wherein Exe2x80x2, Gxe2x80x2, Qxe2x80x2, Q, and n are as defined above.
In a seventh aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (II) or its pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite and a pharmaceutically acceptable carrier.
In an eighth aspect, the invention relates to a method of treating a neurological disorder in an animal, comprising administering to the animal a therapeutically effective amount of a compound of formula (H) or its pharmaceutically acceptable salt, solvate, prodrug, or its pharmaceutically active metabolite.
In a ninth aspect, the invention relates to processes of making the compounds of formula (II).
In a tenth aspect, the invention relates to a method of treating hair loss, memory impairment, or vision disorder in an animal comprising administration to the animal a therapeutically effective amount of a compound of formula (II) or its pharmaceutically acceptable salt, prodrug, solvate, or its pharmaceutically active metabolite.
In an eleventh aspect, the invention relates to a process of producing a compound of formula (II) comprising reacting a sulfamoyl halide and an amine in the presence of lutidine (preferably 3,5-lutidine) to produce the compound.
Other features, objects, and advantages of the invention will become apparent from the following detailed description of the invention.
As used in the present application, unless otherwise stated, the following definitions apply:
In accordance with a convention used in the art, 
is used in structural formulas herein to depict the bond that is the point of attach t of the moiety or substituent to the core or backbone structure.
Where chiral carbons are included in chemical structures, unless a particular orientation is depicted, both sterioisomeric forms are intended to be encompassed.
An xe2x80x9calkyl groupxe2x80x9d is intended to mean a straight- or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl (Bu), isobutyl, t-butyl (t-Bu), ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below (e.g., one or more halogens, such as F, Cl, Br, or I, with F and Cl being preferred). A xe2x80x9clower alkyl groupxe2x80x9d is intended to mean an alkyl group having from 1 to 4 carbon atoms in its chain.
A xe2x80x9ccycloalkyl groupxe2x80x9d is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more substituents. Illustrative examples of cycloalkyl groups include the following moieties: 
A xe2x80x9cheterocycloalky groupxe2x80x9d is intended to mean a non-aromatic monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, which includes 1, 2, 3, 4, or 5 heteroatoms selected nitrogen, oxygen, and sulfur, where the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include the following moieties: 
An xe2x80x9caryl groupxe2x80x9d is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Thus, the term xe2x80x9caryl groupxe2x80x9d includes a benzyl group (Bzl). Illustrative examples of aryl groups include the following moieties: 
A xe2x80x9cheteroaryl groupxe2x80x9d is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include the following moieties: 
A xe2x80x9cheterocyclexe2x80x9d is intended to mean a heteroaryl or heterocycloalkyl group (each of which, as defined above, are optionally substituted).
An xe2x80x9cacyl groupxe2x80x9d is intended to mean a xe2x80x94C(O)xe2x80x94R radical, where R is a substituent as defined below.
A xe2x80x9cthioacyl groupxe2x80x9d is intended to mean a xe2x80x94C(S)xe2x80x94R radical, where R is a substituent as defined below.
A xe2x80x9csulfonyl groupxe2x80x9d is intended to mean a xe2x80x94SO2R radical, where R is a substituent as defined below.
A xe2x80x9chydroxy groupxe2x80x9d is intended to mean the radical xe2x80x94OH.
An xe2x80x9camino groupxe2x80x9d is intended to mean the radical xe2x80x94NH2.
An xe2x80x9calkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NHRa, where Ra is an alkyl group.
A xe2x80x9cdialkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NRaRb, where Ra and Rb are each independently an alkyl group.
An xe2x80x9calkoxy groupxe2x80x9d is intended to mean the radical xe2x80x94ORa, where Ra is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like.
An xe2x80x9calkoxycarbonyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)ORa, where Ra is an alkyl group.
An xe2x80x9calkylsulfonyl groupxe2x80x9d is intended to mean the radical xe2x80x94SO2Ra, where Ra is an alkyl group.
An xe2x80x9calkylaminocarbonyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)NHRa, where Ra is an alkyl group.
A xe2x80x9cdialkylaminocarbonyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)NRaRb, where Ra and Rb are each independently an alkyl group.
A xe2x80x9cmercapto groupxe2x80x9d is intended to mean the radical xe2x80x94SH.
An xe2x80x9calkylthio groupxe2x80x9d is intended to mean the radical xe2x80x94SRa, where Ra is an alkyl group.
A xe2x80x9ccarboxy groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)OH.
A xe2x80x9ccarbamoyl groupxe2x80x9d is intended to mean the radical xe2x80x94C(O)NH2.
An xe2x80x9caryloxy groupxe2x80x9d is intended to mean the radical xe2x80x94ORc, where Rc is an aryl group.
A xe2x80x9cheteroaryloxy groupxe2x80x9d is intended to mean the radical xe2x80x94ORd, where Rd is a heteroaryl group.
An xe2x80x9carylthio groupxe2x80x9d is intended to mean the radical xe2x80x94SRc, where Rc is an aryl group.
A xe2x80x9cheteroarylthio groupxe2x80x9d is intended to mean the radical xe2x80x94SRd, where Rd is a heteroaryl group.
The term xe2x80x9csuitable organic moietyxe2x80x9d is intended to mean any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like.
The term xe2x80x9csubstituentxe2x80x9d or xe2x80x9csuitable substituentxe2x80x9d is intended to mean any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art. Illustrative examples of suitable substituents include hydroxy groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, and the like.
The term xe2x80x9coptionally substitutedxe2x80x9d is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents. As defined above, various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specified group is unsubstituted).
A xe2x80x9cprodrugxe2x80x9d is intended to mean a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound that is pharmaceutically active.
A xe2x80x9cpharmaceutically active metabolitexe2x80x9d is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound.
Prodrugs and active metabolites of compounds of the formula I, or II may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan, et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
A xe2x80x9csolvatexe2x80x9d is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophaosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1, 4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phylacetates, phenylpropionates, phylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the neurotrophic compound of formula I or II is a base, a desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acid, such as glucuronic acid or galacturonic acid; alpha-hydroxy acid, such as citric acid or tartaric acid; amino acid, such as apsartic acid or glutamic acid; aromatic acid, such as benzoic acid or cinnamic acid; sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid; or the like.
If the neurotrophic compound of formula I or II is an acid, a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that they may exist in different crystal forms, all of which are intended to be within the scope of the present invention and specified formulas.
The neurotrophic compounds of formula I, and II and the intermediates used in the process of the present invention, may exist as single stereoisomers, racemates, and/or mixtures of enantiometers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the broad scope of the nonstereospecific structural formulae. Preferably, however, the compounds of formula I and II and the intermediate compounds used in the process of the present invention are used in optically pure form.
As generally understood by those skilled in the art, an optically pure compound is one that is enantiomerically pure. As used herein, the term xe2x80x9coptically purexe2x80x9d is intended to mean a compound comprising at least a sufficient amount of a single enantiomer to yield a compound having the desired pharmacological activity. Preferably, xe2x80x9coptically purexe2x80x9d is intended to mean a compound that comprises at least 90% of a single isomer (80% enantiomeric excess (e.e.)), more preferably at least 95% (90% e.e.), even more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.). Preferably, the neurotrophic compounds of the present invention are optically pure.
Neurotrophic compounds of the invention are represented by the formula (I) and (II) defined above. Preferably, the neurotrophic compounds inhibit the rotamase (peptidyl-prolyl isomerase) enzyme activity of FKBP, in particular, FKBP12. In addition to compounds of the formula (I) and (II), neurotrophic compounds of the invention include pharmaceutically acceptable derivatives of such compounds, such as prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates thereof.
Particularly preferred are compounds of the formula (Ixe2x80x2): 
wherein A, B, D, E and X are as previously defined for the compound of formula (I).
Preferably, A is an unbranched C3-C5 alkylene group wherein any one of the CH2 groups of the alkylene group is optionally substituted by S. More preferably, A is an unbranched unsubstituted C3 or C4 alkylene group (i.e., 1,3-propylene or 1,4-butylene). Even more preferably, A is C4 alkylene.
Preferably, B is 
wherein E is selected from the group consisting of H, benzyl, 3-pyridyl, 2-phenylethyl and 3-phenylpropyl; G is selected from the group consisting of phenyl, 3-pyridyl, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxyphenyl; and n is 0-4. More preferably B is selected from the group consisting of: 
Preferably, D is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1-(5-N,N-dimethylamino)-naphthyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, 1,1-dimethylpropyl and E-styrenyl. Even more preferably D is selected from the group consisting of phenyl, 1,1-dimethylpropyl and 3,4,5-trimethoxyphenyl.
Preferably, X is NH or O.
Especially preferred species of compounds represented by the above formula (I) are the following: 
Especially preferred moieties for the variables of formula (II) are presented below and in the following examples.
Preferred examples of Jxe2x80x2 are hydrogen, (C1-C5) alkyl which can be substituted with substituted or unsubstituted aryl, such as phenyl or halogenated phenyl.
Preferred examples of Kxe2x80x2 are (C1-C5) alkyl which can be substituted with substituted or unsubstituted aryl, such as phenyl or halogenated phenyl;
Alternatively, Jxe2x80x2 and Kxe2x80x2 taken together with the adjacent nitrogen atom form a 5-7 membered heterocycle ring which may contain another heteroatom such as S, and O, and moieties selected from SO2, and NR, wherein R is selected from hydrogen, and substituted or unsubstituted alkyl, aryl and heteroaryl; or Jxe2x80x2 and Kxe2x80x2 taken together with the adjacent nitrogen atom form azo-bicyclo[2.2.1] heptane or azo-bicyclo[2.2.2] octane optionally substituted with substituted or unsubstituted alkyl or aryl or one or more halogens;
In preferred embodiments, R1 is C4-C6 cycloalkenyl, hydroxy, halogen, hydroxyl, NO2, CF3, C1-C6 alkyl, C2-C6 alkenyl, C4 alkenyloxy, benzyloxy, phenoxy, amino, phenyl, or C1-C4 alkyloxy. R11 and R12 can each independently be C1-C6 alkyl. R13 R can be C1-C6, or (CH2)nxe2x80x94Oxe2x80x94W1, where n is 0, 1, 2, or 3, W1 is R2 or C(O)R2, and R2 is C1-C3 alkyl optionally substituted with, for example, one or two methoxy groups.
A preferred Rxe2x80x2 group is (C1-C5) alkyl. Alternatively, RI and Rxe2x80x2 taken together with an adjacent nitrogen atom can form a substituted or unsubstituted heterocycle, which can be saturated or unsaturated or aromatic and can be substituted with, e.g., C1-C4 alkyl, hydroxy or halogen;
Preferred examples of Rxe2x80x3 are hydrogen or substituted or unsubstituted (C1-C5) alkyl. Alternatively, R1 and Rxe2x80x3 taken together with an adjacent nitrogen form a substituted or unsubstituted heterocycle, which can be saturated or unsaturated or aromatic and can be substituted with, e.g., (C1-C4) alkyl, hydroxy or halogen.
Preferred examples of Yxe2x80x2 are a direct bond or NRf, wherein Rf is (C1-C5) alkyl which may be substituted with, e.g., phenyl or halogenated phenyl.
Preferred examples of Exe2x80x2 and Gxe2x80x2 are C1-C6 straight or branched alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkyl or alkenyl that is substituted with a C5-C7 cycloalkyl, C1-C6 straight or branched alkyl or alkenyl that is substituted with a C5-C7 cycloalkenyl, or heterocycle substituted with C1-C6 straight or branched alkyl or alkenyl.
Preferred examples of Qxe2x80x2 are C1-C6 straight or branched alkyl or C1-C6 straight or branched alkenyl.
Preferred examples of Q are substituted 5-7 membered cycloalkyl with substituents at positions 3 and 4 which are independently selected from H, OH, xe2x80x94Oxe2x80x94(CH2)m-alkyl, xe2x80x94Oxe2x80x94(CH2)m-alkenyl and carbonyl, wherein m is 1-4.
Preferred examples of useful aryl and heteroaryl groups for the compounds of formula (II), such as for Exe2x80x2, Gxe2x80x2, and Q, are phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which may contain in either or both rings a total of 1-4 heteroatoms independently selected from O, N and S. The aryl and heteroaryl groups may contain one to three substituents independently selected from hydrogen, halo, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 straight and branched alkyl, C2-C6 straight and branched alkenyl, Oxe2x80x94(C1-C4 straight and branched alkyl), Oxe2x80x94(C2-C4 straight and branched alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl;
Preferred examples of Ra and Rb are (C1-C5) alkyl with or without, for example, aryl substitution, or (C3-C7) cycloalkyl.
Preferred example of Z is NRe, wherein Re is (C1-C4) alkyl which may be substituted with phenyl or halogenated phenyl.
The compounds of the invention also include pharmaceutically acceptable derivatives of compounds of the formula (I) and (II). A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d denotes a prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt, ester, salt of such ester, or hydrate of a compound of this invention. Such compounds, when administered to a patient, are capable of directly or indirectly yielding a compound of this invention, or a metabolic residue or product thereof, and thereby inhibit FKBP rotamase activity or promote or augment neurite outgrowth.
The compounds of formula (I) and (II) as well as metabolites thereof may be used in pharmaceutical compositions in the form of pharmaceutically acceptable salts. Such salts are preferably derived from inorganic or organic acids and bases. Exemplary acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Exemplary base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucosamine salt, and salts with amino acids such as arginine and lysine. Also, the basic nitrogen-containing groups can be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides or iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides; and aralkyl halides, such as benzyl and phenethyl bromides. Water- or oil-soluble or dispersible products may be prepared from such salts.
In addition, the compounds of the invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications, which are within the purview of the ordinarily skilled artisan, include those increasing biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increasing oral availability, increasing solubility to allow administration by injection, altering metabolism, and altering rate of excretion.
Some of the compounds described herein contain one or more centers of asymmetry and may thus give rise to enantiomers, diastereoisomers, rotamers, and other stereoisomeric forms. The present invention is meant to include all such possible stereoisomers as well as their racemic and optically pure forms. Optically active (R) and (S) isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds, they are intended to include both E and Z geometric isomers.
Moreover, the chemical formulae referred to herein may exhibit the phenomenon of tautomerism. As the formulae drawings within this specification can only represent one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form that can be generated by employing the tools disclosed or in a known manner, and is not limited to any one tautomeric form depicted by the formulae.